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Regular and Young Investigator Award Abstracts
Immuno-Engineering
1113 Engineering vaccines against S100A9 to treat cancer co-morbidities
  1. Debbie K Ledezma1,2,
  2. Jessica F Affonso de Oliveira1 and
  3. Nicole F Steinmetz2,3,4,5,6,7,8,9,10
  1. 1University of California San Diego, La Jolla, CA, USA
  2. 2Moores Cancer Center, University of California, University of California San Diego,, La Jolla, CA, USA
  3. 3Shu and K.C. Chien and Peter Farrell Collaboratory, University of California San Diego, La Jolla, CA, USA
  4. 4Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
  5. 5Institute for Materials Discovery and Design, University of California San Diego, La Jolla, CA, USA
  6. 6Nanotechnology Characterization Laboratory, Frederick, MD, USA
  7. 7Department of Radiology, University of California San Diego, La Jolla, CA, USA
  8. 8Center for Engineering in Cancer, Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA
  9. 9Center for Nano-ImmunoEngineering, University of California San Diego, La Jolla, CA, USA
  10. 10Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California San Diego, La Jolla, CA, USA

  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract

Background Chronic inflammation is linked to various diseases associated with cancer co-morbidities, which negatively impact cancer prognosis. One major regulator of inflammation is calcium-binding protein S100A9. It can broadly regulate myeloid and monocyte-derived immune populations.1 2 Further, high S100A9 expression has been implicated in multiple cancers and metastasis, suggesting its potential role in cancer-associated inflammatory dysregulation. Interestingly, higher S100A9 is also a potential marker for cardiovascular risk.3 Engineered vaccines against S100A9 reduced the onset of lung metastasis4 and atherosclerosis independently,5 yet the benefit of S100A9 inhibition in a co-morbidity setting is not yet known. Here, we aim to evaluate immune-engineered vaccines against S100A9 in a pre-clinical co-morbidity model as a potential therapeutic target for cancer patients presenting co-morbidities.

Methods We engineered peptide vaccines by chemically conjugating S100A9 B-cell epitope peptide onto different virus-like particles (VLPs) to elicit anti-S100A9 titers. After vaccinating C57BL/6 mice, anti-S100A9 titers were evaluated to determine S100A9 affinity, avidity, and Th-bias using ELISA. Vaccinated mice were then intravenously challenged with B16F10 melanoma cells to examine the vaccine-induced protection against lung metastasis. Lung nodules were manually counted. Splenocytes from vaccinated mice were evaluated via IFN-γ ELISpot to assess break of immune-tolerance.

Results In the B16F10 lung metastasis model, vaccination with VLP2-S100A9 demonstrated trending significance in reducing lung nodules compared to VLP1-S100A9 (figure 1). Antibody evaluation demonstrates that while both vaccine candidates generate a Th1-biased response after the first two vaccines, VLP1-S100A9 maintains Th1-bias after the third vaccine, while VLP2-S100A9 switches to a Th2-bias (figure 2A). However, VLP2-S100A9 generates significantly more titers and with higher avidity than VLP1-S100A9 (figure 2B), suggesting VLP2 is a promising adjuvant. VLP2, as a stimulant, stimulated comparable activation in splenocytes from all groups, while VLP1 only activated splenocytes derived from VLP1-S100A9 and Mixture mice. Splenocytes co-incubated with B16F10 cells showed similar activation levels, regardless of group. Thus, the vaccines likely did not induce tumor killing but rather modulated the lung microenvironment to reduce tumor seeding, similarly to what our group reported4. Future work using ApoE-/- mice on high-fat diet will assess if our engineered vaccines concurrently reduce metastasis and plaque formation. Critical evaluation in a cancer-cardiovascular model will provide important insight into treating cancer co-morbidities.

Conclusions In this study, our goal is to inhibit an inflammatory protein associated with cancer and cancer-morbidities. We envision the innovative engineering of vaccines against markers associated with cancer and commonly reported co-morbidities will provide an encompassing therapeutic approach for cancer co-morbidity cases.

Acknowledgements We would like to acknowledge the following funding sources: NIH award R01-CA224605, R01-CA253615, and T32CA121938. We want to thank the UCSD Chancellor’s Fellowship and SD IRACDA Program for supporting Dr. Ledezma. We also appreciate the technical support provided by the UCSD veterinarians for this study.

References

  1. Markowitz J, Carson WE. Review of S100A9 biology and its role in cancer. Biochim. Biophys. Acta 2013;1835(1):100–109.

  2. Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J. Exp. Med. 2008;205(10):2235–2249.

  3. Healy AM, Pickard MD, Pradhan AD, Wang Y, Chen Z, Croce K, Sakuma M, Shi C, Zago AC, Garasic J, Damokosh AI, Dowie TL, Poisson L, Lillie J, Libby P, Ridker PM, Simon DI. Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation. 2006;113:2278–2284.

  4. Chung YH, Ortega-Rivera OA, Volckaert BA, Jung E, Zhao Z, Steinmetz NF. Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis. Proc Natl Acad Sci U S A. 2023 Oct 24;120(43):e2221859120.

  5. Ortega-Rivera OA, Shin MD, Moreno-Gonzalez MA, Pokorski JK, Steinmetz NF. A single-dose Qβ VLP vaccine against S100A9 protein reduces atherosclerosis in a preclinical model. Adv Ther (Weinh). 2022 Oct;5(10):2200092.

Ethics Approval The present study was approved by the institutional IACUC (protocol number S18021) and all institutional guidelines were followed.

Abstract 1113 Figure 1
Abstract 1113 Figure 1

Quantitative analysis of B16F10 tumor nodules within the lungs (N=4)

Abstract 1113 Figure 2
Abstract 1113 Figure 2

Evaluation of antibodies generated by S100A9 vaccines. A) Th-bias response of both vaccines was determined as the independent ratio of IgG2a and IgG2b to IgG1, after the second vaccine (week 4, right) and third vaccine (week 6, left). B) Titers against S100A9 peptide (left), and the avidity index of the anti-

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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2024-SITC2024.1113

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